title: Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells.
abstract: Under hypoxia, cancer cells consume glucose and release lactate at a high rate. Lactate was recently documented to be recaptured by oxygenated cancer cells to fuel the TCA cycle and thereby to support tumor growth. Monocarboxylate transporters (MCT) are the main lactate carriers and therefore represent potential therapeutic targets to limit cancer progression. In this study, we have developed and implemented a stepwise in vitro screening procedure on human cancer cells to identify new potent MCT inhibitors. Various 7-substituted carboxycoumarins and quinolinone derivatives were synthesized and pharmacologically evaluated. Most active compounds were obtained using a palladium-catalyzed Buchwald-Hartwig type coupling reaction, which proved to be a quick and efficient method to obtain aminocarboxycoumarin derivatives. Inhibition of lactate flux revealed that the most active compound 19 (IC50 11 nM) was three log orders more active than the CHC reference compound. Comparison with warfarin, a conventional anticoagulant coumarin, further showed that compound 19 did not influence the prothrombin time which, together with a good in vitro ADME profile, supports the potential of this new family of compounds to act as anticancer drugs through inhibition of lactate flux.
authors.affiliation: UCL/SSS/IREC/FATH, Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue E. Mounier 53, B1.53.09, B-1200 Brussels, Belgium; Molecules, Solids and Reactivity (MOST), Institute of Condensed Matter and Nanosciences (IMCN), UCLouvain, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Nihed
authors.initials: N
authors.lastname: Draoui
authors.forename: Olivier
authors.initials: O
authors.lastname: Schicke
authors.forename: Antony
authors.initials: A
authors.lastname: Fernandes
authors.forename: Xavier
authors.initials: X
authors.lastname: Drozak
authors.forename: Fady
authors.initials: F
authors.lastname: Nahra
authors.forename: Amélie
authors.initials: A
authors.lastname: Dumont
authors.forename: Jonathan
authors.initials: J
authors.lastname: Douxfils
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hermans
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Romu
authors.initials: R
authors.lastname: Corbau
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchand
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaltin
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.forename: Olivier
authors.initials: O
authors.lastname: Riant
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007773:Lactates / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry
chemical_list: C588295:7-(N-benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid; D000970:Antineoplastic Agents; D003374:Coumarins; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D015363:Quinolones
keywords: Cancer; Carboxycoumarins; Lactate; Monocarboxylate transporter